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Abnormal resting state functional connectivity of the periaqueductal grey in patients with fibromyalgia

May 2016
Clinical and Experimental Rheumatology 34(2 Suppl 96):129-33

Authors:

Andrea Truini

Sapienza University of Rome

Emanuele Tinelli

Magna Graecia University

Maria Chiara Gerardi

Rheumatology and Clinical Immunology Unit and Department of Clinical and Experimental Sciences

Valentina Calistri

Sapienza University of Rome

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Objectives: Emerging evidence associates chronic pain syndrome, such as fibromyalgia, with endogenous pain modulatory system dysfunction, leading to an impaired descending pain inhibition. In this study, using resting-state functional magnetic resonance imaging (fMRI), we aimed at seeking possible functional connectivity changes of the periaqueductal gray (PAG), a brainstem area that belongs to the endogenous pain modulatory system, in patients with fibromyalgia. Methods: In 20 patients with fibromyalgia and 15 healthy subjects, we investigated PAG functional connectivity using resting-state fMRI. We also analysed the correlation between clinical variables, such as pain severity, disease duration, and depressive personality traits with PAG functional connectivity. Results: Compared with control subjects, we identified that patients with fibromyalgia had an increased PAG connectivity with insula, anterior cingulate cortex, and anterior prefrontal cortex. The functional connectivity between PAG and the rostral ventral medulla, however, was not concordantly increased. PAG functional connectivity correlated with pain severity, disease duration, and the depressive personality trait rating. Conclusions: Our fMRI study showing abnormal resting state functional connectivity of the PAG suggests that patients with fibromyalgia have an endogenous pain modulatory system dysfunction, possibly causing an impaired descending pain inhibition. This abnormal PAG functioning might underlay the chronic pain these patients suffer from.

Statistical maps of positive functional resting state connectivity with the PAG in (A) 20 fibromyalgia patients and in (B) 15 age and gender matched healthy controls. Statistical threshold corresponded to Z>3 and a correct cluster significance of p<0.05.

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1Department of Neurology and Psychiatry,

Sapienza University of Rome, Italy;

2Rheumatology Unit, Department of

Internal Medicine and Medical Specialties,

Sapienza University of Rome, Italy;

3Rheumatology Unit, Luigi Sacco

University Hospital, Milan, Italy;

4Athinoula A. Martinos Center for

Biomedical Imaging, Massachusetts

General Hospital, Boston, MA, and

Harvard Medical School, Boston,

MA, USA.

Andrea Truini, MD*

Emanuele Tinelli, MD*

Maria Chiara Gerardi, MD

Valentina Calistri, MD

Cristina Iannuccelli, MD

Silvia La Cesa, MD

Lorenzo Tarsitani, MD

Caterina Mainero, MD

Piercarlo Sarzi-Puttini, MD

Giorgio Cruccu, MD

Francesca Caramia, MD

Manuela Di Franco, MD

*These authors equally contributed

to the study.

Please address correspondence to:

Maria Chiara Gerardi, MD,

Rheumatology Unit,

Luigi Sacco University Hospital,

Via G.B. Grassi,

20157 Milan, Italy.

E-mail: mariachiara.gerardi@gmail.com

Received on February 13, 2016; accepted

in revised form on March 24, 2016.

Clin Exp Rheumatol 2016; 34 (Suppl. 96):

S129-S133.

EXPERIMENTAL RHEUMATOLOGY 2016.

Key words: bromyalgia,

magnetic resonance imaging,

periaqueductal grey, endogenous

pain modulatory system

Competing interests: none declared.

ABSTRACT

Objective. Emerging evidence associ-

ates chronic pain syndrome, such as

bromyalgia, with endogenous pain

modulatory system dysfunction, lead-

ing to an impaired descending pain

inhibition. In this study, using resting-

state functional magnetic resonance

imaging (fMRI), we aimed at seeking

possible functional connectivity chang-

es of the periaqueductal gray (PAG), a

brainstem area that belongs to the en-

dogenous pain modulatory system, in

patients with bromyalgia.

Methods. In 20 patients with bromy-

algia and 15 healthy subjects, we in-

vestigated PAG functional connectivity

using resting-state fMRI. We also ana-

lysed the correlation between clinical

variables, such as pain severity, disease

duration, and depressive personality

traits with PAG functional connectivity.

Results. Compared with control sub-

jects, we identied that patients with

bromyalgia had an increased PAG

connectivity with insula, anterior cin-

gulate cortex, and anterior prefrontal

cortex. The functional connectivity be-

tween PAG and the rostral ventral me-

dulla, however, was not concordantly

increased. PAG functional connectivity

correlated with pain severity, disease

duration, and the depressive personal-

ity trait rating.

Conclusion. Our fMRI study show-

ing abnormal resting state functional

connectivity of the PAG suggests that

patients with bromyalgia have an en-

dogenous pain modulatory system dys-

function, possibly causing an impaired

descending pain inhibition. This abnor-

mal PAG functioning might underlay the

chronic pain these patients suffer from.

Introduction

The pathophysiology of bromyal-

gia (FM) is still unclear (1, 2). Many

studies showing that as well as caus-

ing widespread pain and fatigue FM

causes sleep disturbances, mood disor-

ders, and neurocognitive impairment,

led some to postulate a central nervous

system dysfunction including pain ma-

trix hyperexcitability and endogenous

pain modulatory system abnormalities,

leading to an impaired descending pain

inhibition (3-9).

In a recent neurophysiological study,

we have showed that patients with FM

have signs of pain matrices hyperexcit-

ability (9), probably contributing to the

different symptoms patients with this

condition experience. However, in this

study we did not provide any informa-

tion on how FM pathophysiology in-

volves descending modulatory system

structures, such as the periaqueductal

gray (PAG). The PAG receives projec-

tions from the anterior cingulate cortex

and modulates pain perception through

brain stem structures, such as the Ros-

tral Ventral Medulla (RVM), which

directly sends inhibitory projections to

the nociceptive dorsal horn neurons of

the spinal cord (10). Given that PAG

modulates pain perception, an abnor-

mal PAG activity might underlie pain in

patients with FM (11, 12). Having more

information on the descending modula-

tory system function might be relevant

to the pharmacological treatment of

pain in this disease, lending a rational

support to the use of antidepressants.

Continuing our research activity into

the mechanisms underlying FM (9)

and the endogenous pain modulatory

system (11) in this clinical and neuro-

imaging study we sought possible PAG

abnormalities in patients with FM. To

do so, using functional magnetic reso-

nance imaging (fMRI), we have inves-

tigated the resting state functional con-

nectivity of PAG in 20 patients with

FM and in 15 healthy controls.

Abnormal resting state functional connectivity of the

periaqueductal grey in patients with bromyalgia

A. Truini1, E. Tinelli1, M.C. Gerardi2, V. Calistri1, C. Iannuccelli2, S. La Cesa1,

L. Tarsitani1, C. Mainero4, P. Sarzi-Puttini3, G. Cruccu1, F. Caramia1, M. Di Franco2

S-130

bnormal resting state in patients with bromyalgia   ruini et al

Methods

Patients

We pro sp ec ti ve ly en ro ll ed 20 con se cu -

tive patients (19 F, 1 M; aged 28-67

years) referred to the Fibromyalgia

Clinic at the Rheumatology Unit, De-

partment of Internal Medicine and Med-

ical Specialties, Sapienza University of

Rome, and 15 healthy, matched subjects

(F 13, 2 M; aged 26-65 years). Inclu-

sion criteria for patients were: patients

aged >18 years; a medically conrmed

diagnosis of FM according both 1990

and 2010 American College of Rheu-

matology criteria (13-15) and willing-

ness to participate in the experimental

procedures. Exclusion criteria included

all autoimmune and rheumatic diseases,

other and additional pain sources (in-

cluding pain due to osteoarthritis) and

neurological and psychiatric diseases,

including major depression. None of the

participants was taking pain medication

potentially affecting the PAG connec-

tivity, such as antidepressants, opioids

or antiepileptics. Pregnancy was also

an exclusion criterion for both patients

and controls. The local Institutional Re-

view Board approved the study and all

patients and healthy volunteers gave in-

formed consent.

All patients underwent clinical exami-

nation at the Rheumatology Unit. The

Manual Tender Point Survey was used

to rate the severity of pain elicited by

palpating the 18 tender points dened

by the American College of Rheuma-

tology (16). We also collected the Zung

Self-Rating Depression (ZSDS) and

Anxiety Scales (ZSAS) (17, 18). We

used a visual analogue scale (VAS) for

assessing pain severity, at the time of

examination.

After the rheumatologic examination,

all the patients underwent MRI acqui-

sition at the Department of Neurol-

ogy and Psychiatry. They were asked

to avoid occasional (rescue) analgesic

drugs 72 hours prior to fMRI.

MRI acquisition and statistical

analysis

All subjects underwent anatomical and

functional scanning on a 3 Tesla Sie-

mens-Verio scanner in a single session

equipped with a 12 channel head-coil.

rs-fMRI data of bromyalgia patients

were compared to those of 15 aged

matched healthy controls. During the

resting-state, subjects were instructed

to keep their eyes closed and to remain

motionless and to not think of anything

in particular. To minimise motion arte-

facts, subjects lay supine with pillows

under the head, foam wedges at the

sides and a retaining strap. For each

subject images were obtained using

a interleaved double-echoTurbo Spin

Echo sequence proton density and T2-

weighted images (repetition time: 3320

ms, echo time: 10/103 ms, matrix: 384

× 384, eld of view: 220 mm, slice

thickness: 4 mm, gap: 1.2 mm, 50 axial

slices) and 3D T1-weighted MPRAGE

(repetition time: 2300 ms, echo time:

2.98 ms, inversion time: 900 ms, ip

angle: 9°, eld of view: 256 mm, 208

slices in the sagittal plane, 1 mm iso-

metric voxel). rs-fMRI study was per-

formed with single-shot EPI images

(repetition time: 3000 ms, echo time:

30 ms, ip angle: 90°, eld of view: 240

mm, 46 axial slices, thickness: 3 mm,

140 volumes).

A seed analysis approach was per-

formed to identify those voxels show-

ing functional signal time-courses

correlated with the PAG. Seeds were

manually selected in standard space

based on the anatomy; the right and left

PAG were selected as regions of inter-

est (peak MNI coordinates: left PAG=

-2; -28; -6; right PAG= 4; -28; -6, with

3 mm radius).

Functional data were processed us-

ing FSL as described previously (19),

including motion correction, spatial

smoothing with 5mm full width half

maximal Gaussian kernel, and a tem-

poral high-pass lter. MELODIC In-

dependent Component Analysis (ICA)

was performed in order to identify

and remove noisy components due to

scanner-related and physiological arte-

facts from the 4D fMRI data. Nonlinear

registration using FMRIB’s Nonlinear

Image Registration Tool (FNIRT) was

applied between the subject’s structural

and the standard space (the Montreal

Neurological Institute 2mm brain) (20).

Average time courses were extracted

from seeds using FSL’s feat query func-

tion. The pre-processed time series

were then tted with a linear model

consisting of a regressor representing

the extracted time courses. The spa-

tially normalised effect size and stand-

ard error volumes served as input to a

mixed effects group analysis in FSL

FEAT. The modeled group effect size

and standard error were then divided to

produce a volume whose voxels were

t scores, subsequently transformed to

Z scores. Within and between groups

comparisons of correlation effect size

were performed using one sample t-

test in each group and unpaired t-test

in patients versus controls. Images and

were thresholded using clusters deter-

mined by Z>3 (within group) and Z>2

(between group) and a corrected cluster

signicance threshold of p<0.05, in-

cluding at least 20 contiguous voxels.

We did not detect laterality differences

between the two seed used.

Results

In both healthy subjects and patients,

PAG showed positive functional con-

nectivity with brain structures related

to the endogenous pain modulatory

system and the pain matrices, such as

prefrontal cortex, insula, anterior cin-

gulate cortex (ACC) and RVM (Fig. 1;

Table I, II). Compared to the healthy

subjects, patients with FM had a PAG

increased connectivity with the ACC,

amygdala and insula but not with RVM

(Fig. 2; Table III).

Clinical-MRI correlation showed that

the disease duration correlated with the

connectivity between PAG and insula

and bilateral temporal poles (Z> 2.3,

corrected clusters p<0.05). The sever-

ity of pain elicited by pressing the ten-

der points correlated with the connec-

tivity between PAG and inferior frontal

gyrus, precuneus, insula and opercu-

lar cortex (Z> 2.3, corrected clusters

p<0.05). More specically, the longer

the duration and the higher the pain

scores, the higher the PAG functional

connectivity.

Depression as assessed with the ZSDS

correlated with the connectivity be-

tween PAG and opercular cortex, su-

perior frontal gyrus and supramar-

ginal gyrus (Z> 2.3, corrected clusters

p<0.05). More specically the higher

the depression rating scores, the lower

the PAG functional connectivity.

S-131

bnormal resting state in patients with bromyalgia   ruini et al

Discussion

Our clinical and neuroimaging study

in patients with FM showed an abnor-

mal PAG resting state functional con-

nectivity: while the PAG connectivity

with ACC is enhanced, that with RVM

is not concordantly increased. This un-

balanced PAG functional connectivity

might entail an impaired descending

pain inhibition, possibly underlying

pain in patients with FM.

To investigate mechanisms underlying

FM, a challenging task, we concentrat-

ed on PAG, being a converging brain

area for pain modulation and playing a

key role in the endogenous pain modu-

latory system (21). Several observa-

tions suggest that the descending pain

modulatory system dysfunction con-

tributes to the development of chronic

pain conditions such as headache and

low back pain (10, 22). To seek infor-

mation on PAG function in patients

with FM we have used resting-state

fMRI. This technique measures uc-

tuations in the blood oxygenation level

in the brain, thought to be representa-

tive of neuronal activity. Functional

connectivity measures the degree to

which two brain regions have synchro-

nous uctuations in activity over time;

regions with similar uctuations are

referred to as highly functionally con-

nected. Hence, the resting state fMRI

showing the PAG functional connectiv-

ity provides reliable information on the

endogenous pain modulatory system

and the brain areas functionally con-

nected with the PAG.

We found that patients with FM have

an increased PAG functional connec-

tivity with several pain-related brain

areas, such as the anterior cingulate

cortex, insula, and amygdala. We hy-

pothesise that the increased functional

connectivity between PAG and these

areas, including the ACC, presumably

reects the chronic pain these patients

were suffering from. This hypothesis

Fig. 1. Statistical maps of positive functional resting state connectivity with the PAG in (A) 20 bromyalgia patients and in (B) 15 age and gender matched

healthy controls. Statistical threshold corresponded to Z>3 and a correct cluster signicance of p<0.05.

Table I. Functional connectivity of PAG during resting state in 15 control subjects demon-

strating positive correlations between brain areas and PAG.

MNI

coordinates

x y z Z max

PAG and surrounding areas (midbrain, hypotalamus, 4 -28 -6 5.2

striatum, globus palludum, thalamus)

Paracingulate BA 8 4 32 40 5

R - Superior frontal gyrus BA 8 4 28 50 4.8

L - Cerebellum -10 -70 -28 4.8

R - Insula 36 20 -4 4.7

R - Cerebellum 20 -70 -38 4

L - Insula -40 0 -10 3.8

ACC 6 36 8 3.8

RVM 2 -38 -52 3.1

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bnormal resting state in patients with bromyalgia   ruini et al

is in line with human studies showing

that the PAG activity increases during

pain (23), and this activation correlates

with the severity of pain (11). Our nd-

ings on an increased PAG functional

connectivity clash with two previous

fMRI resting state studies (8, 24) that

showed an overall reduction of rest-

ing state functional connectivity, and

more specically a hypo-connectivity

between PAG and insula and amyg-

dala. The contrasting results probably

reect the different sample sizes and

methodological approaches. One study

included only nine subjects and both

investigated the functional resting state

connectivity of multiple brain regions.

Conversely, in our study we included

twenty patients and selected a priori

the PAG as the region of interest in the

functional resting state analysis. Most

important our patients were not taking

any pain medication such as antide-

pressant, drug potentially affecting the

PAG connectivity.

Unexpectedly, the increased functional

connectivity between PAG and ACC

was not paralleled by a similar increase

of functional connectivity between PAG

and RVM. In normal conditions the in-

creased functional connectivity between

PA G a n d A CC i s f o ll ow e d b y a c o he r-

ent increased connectivity with RVM,

according to a top-down modulation

mechanism (25). This unbalanced PAG

functional connectivity might imply a

descending modulatory system decit.

This decit prevents the activation of

inhibitory projections to the nociceptive

dorsal horn neurons of the spinal cord.

When we analysed the clinical-fMRI

correlations we found that the resting

state functional connectivity between

PAG and the pain-related brain areas,

such as the insula, correlated with the

duration of disease and the pain se-

verity. This nding agrees with pre-

vious observations (26) and supports

the hypothesis that FM-related pain is

directly associated with altered brain

function, more specically the more

severe the disease in terms of duration

and pain severity, the more the resting

state abnormalities. We also found that

the functional connectivity between

PAG and opercular cortex, superior

frontal gyrus and supramarginal gyrus

inversely correlated with depression,

as assessed with the ZSDS. This nd-

ing is in line with a previous study (24)

and might indicate that in patients with

FM the depressive trait directly affects

pain related brain areas. This hypoth-

esis supports the common knowledge

that pain and psychiatric disturbances

are closely related (24-26).

Our study has some limitations. Admit-

tedly, the abnormalities of PAG func-

tional connectivity might merely rep-

resent the consequence, rather than the

cause, of the chronic nociceptive input.

We consider this interpretation unlikely,

however, given that we found a pecu-

liar abnormality such as an unbalanced

PAG functional connectivity, namely a

relative reduction of functional connec-

tivity between the PAG and the RVM.

Hence, we hypothesise that the PAG

functional connectivity we describe in

Table II. Functional connectivity of PAG during resting state in 20 bromyalgia patients

demonstrating positive correlations between brain areas and PAG.

MNI

coordinates

x y z Z max

PAG and surrounding areas (midbrain, hypotalamus, -2 -28 -6 5.4

striatum, globus palludum, thalamus)

Precuneous -2 52 52 4.5

L - Amygdala -28 0 -20 4.2

PCC 2 -42 38 4.1

R - Superior parietal lobule BA7 32 -44 42 4

ACC 2 20 20 4

R- Cerebellum 30 -52 -39 4

R - Frontal pole BA 10 36 46 24 4

L - Insula -38 6 -2 3.9

R - Insula 40 0 -8 3.9

L - Amygdala -20 -2 -20 3.9

L -Central opercolar cortex -62 -20 10 3.9

L - Cerebellum -12 -66 -28 3.8

L - Frontal pole BA 10 -38 40 26 3.8

L -Superior parietal lobule BA7 -30 -48 48 3.6

RVM 4 -34 -50 3.6

Fig. 2. Statistical maps of brain regions of increased functional resting state connectivity with the

PAG in 20 bromyalgia patients compared to 15 age and gender matched healthy controls. Statistical

threshold corresponded to Z>2 and a correct cluster signicance of p<0.05.

S-133

bnormal resting state in patients with bromyalgia   ruini et al

patients with bromyalgia probably

plays a direct pathophysiological role in

this disease. Another limitation is that

insofar as our study focuses only on

PAG functional connectivity, we cannot

provide information whether bromy-

algia also involves peripheral nocicep-

tive nerve bres. A recent study using

pain-related evoked potentials and skin

biopsy demonstrated distally distrib-

uted peripheral nervous system dam-

age, selectively involving nociceptive

Aδ- and C-bres (30). Although the pe-

ripheral nerve damage in patients with

bromyalgia still deserves conrma-

tory studies, we hypothesise that bro-

myalgia might be associated with mul-

tiple abnormalities involving both the

central and peripheral nervous system

(31). Further studies investigating both

peripheral and central nervous systems

should therefore verify whether distally

distributed peripheral nervous system

damage and central nervous system ab-

normalities coexist in the same patient.

Our study showing an abnormally un-

balanced PAG functional connectivity

might indicate that in patients with FM

pain is provoked by an impaired de-

scending pain inhibition. The abnormal

PAG functional connectivity correlates

with clinical variables, including the

depressive trait. These ndings lend

strong support to the use of antidepres-

sants in patients with FM, given that an-

tidepressants balance descending mod-

ulatory system and improve depression.

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28. ALOK R, DAS SK, AGARWAL GG, SALWAHAN

L, SRIVASTAVA R: Relationship of severity of

depression, anxiety and stress with severity of

bromyalgia. Clin Exp Rheumatol 2011; 29:

S70-2.

29. VELTRI A, SCARPELLINI P, PICCINNI A et

al.: Methodological approach to depressive

symptoms in bromyalgia patients. Clin Exp

Rheumatol 2012; 30 (Suppl. 74): S136-42.

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that small-ber polyneuropathy underlies

some illnesses currently labeled as bromy-

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Table III. Brain areas with increased connectivity with the PAG during resting state in 20

bromyalgia patients compared to 15 control subjects.

MNI

coordinates

x y z Z max

Caudate -4 12 2 2.6

R - Insula 44 10 -4 2.5

L - Insula -42 4 -4 2.5

R - Frontal pole BA 10 36 48 28 2.4

L - Amygdala -24 0 -26 2.3

L - Central opercolar cortex -54 -12 10 2.3

ACC 2 10 32 2.2

L - Frontal pole BA 10 -36 48 24 2.2

R - Amygdala 16 -2 -18 2.2

Periaqueductal gray connectivity in spinal cord injury-induced neuropathic pain

Article

Full-text available

Sep 2024
J NEUROIMAGING

Background and Purpose Neuropathic pain (NP) is a debilitating condition following spinal cord injury (SCI). The role of periaqueductal gray (PAG) in NP development following SCI remains underexplored. Using resting‐state functional MRI (rsfMRI), our study aimed to demonstrate the alterations in functional connectivity (FC) of PAG in NP following SCI. Methods Ten SCI patients (SCI + NP, n = 7, and SCI − NP, n = 3), alongside 10 healthy controls (HCs), were enrolled. rsfMRI was conducted followed by seed‐to‐voxel analysis using PAG as the seed region and then group‐based analysis comprising three groups (SCI + NP, SCI − NP, and HC). Age and gender were considered as confounding variables. Results Compared to HCs, SCI + NP demonstrated decreased FC between PAG and right insula, right frontal orbital cortex, right pallidum, dorsal raphe nucleus (DRN), red nuclei (RN), substantia nigra (SN), and ventral posterolateral (VPL) thalamic nuclei. Compared to SCI − NP, SCI + NP demonstrated increased FC between PAG and posterior cingulate cortex (PCC), hippocampus, cerebellar vermis lobules IV and V, and thalamic structures (posterior and lateral pulvinar, the mediodorsal nuclei, and the ventral lateral nuclei). Additionally, decreased FC between the PAG and VPL, geniculate bodies, intralaminar nuclei of thalamus, DRN, RN, SN, and prefrontal cortex was observed in this comparison. Conclusions Altered FC between PAG and right anterior insula, VPL, DRN, RN, SN, cerebellar vermis lobules IV and V, frontal cortex, and PCC was associated with NP sequelae of SCI. Additionally, SCI was independently associated with decreased FC between PAG and right posterior insula, cerebellar lobules IV and V, and cerebellar vermis lobules III, IV, and V.

Functional connectivity associated with attention networks differs among subgroups of fibromyalgia patients: an observational case–control study

Article

Full-text available

May 2024

Fibromyalgia is a heterogenous chronic pain disorder diagnosed by symptom-based criteria. The aim of this study was to clarify different pathophysiological characteristics between subgroups of patients with fibromyalgia. We identified subgroups with distinct pain thresholds: those with a low pressure pain threshold (PL; 16 patients) and those with a normal pressure pain threshold (PN; 15 patients). Both groups experienced severe pain. We performed resting-state functional MRI analysis and detected 11 functional connectivity pairs among all 164 ROIs with distinct difference between the two groups (p < 0.001). The most distinctive one was that the PN group had significantly higher functional connectivity between the secondary somatosensory area and the dorsal attention network (p < 0.0001). Then, we investigated the transmission pathway of pain stimuli. Functional connectivity of the thalamus to the insular cortex was significantly higher in the PL group (p < 0.01 – 0.05). These results suggest that endogenous pain driven by top-down signals via the dorsal attention network may contribute to pain sensation in a subgroup of fibromyalgia patients with a normal pain threshold. Besides, external pain driven by bottom-up signals via the spinothalamic tract may contribute to pain sensations in another group of patients with a low pain threshold. Trial registration: UMIN000037712.

Article

Full-text available

Apr 2024
NEUROBIOL AGING

Functional Seizures and Chronic Pain: A Narrative Review of common Pathomechanisms and Clinical Implications

Preprint

Full-text available

Mar 2024

Background Functional seizures (FS) manifest as episodic events, bearing superficial similarities to epileptic seizures and represent a major component of Functional Neurological Disorder (FND). FS frequently present with the co-morbidity of chronic pain and the pronounced clinical and epidemiological associations between these conditions suggest potential shared pathomechanisms. Although conventional neuroimaging and neurophysiological assessments do not detect abnormalities in either condition, advanced biophysical signal analyses offer potential biomarkers. Method We undertook comprehensive literature review encompassing studies employing EEG, MEG, functional MRI, PET, and SPECT in FS and chronic pain. Due to the heterogenous nature of the collected data, the results of data extraction and analysis are presented in the form of a narrative synthesis. Results Despite some limitations, altered neural network dynamics are evident in both FS and chronic pain, revealing intriguing common mechanisms. Both conditions exhibit overactivation in sensorimotor networks and alterations in the Default Mode Network (DMN), impacting self-awareness and pain perception. Emotional processing regions, like the anterior cingulate cortex and insula, were affected in both conditions. Furthermore, Thalamocortical dysrhythmia(TCD) offers an intriguing link, influencing pain perception and seizure-like activities. Finally, suppressed alpha oscillations, linked to sensory perception, are prevalent in both conditions. Conclusion We identified shared neural mechanisms and a possible novel explanation (TCD) for co-occurrence of FS and chronic pain. These necessitate further exploration in subsequent studies incorporating patients exhibiting both disorders concurrently. Such research direction holds the potential to introduce novel therapies for not only managing FS or chronic pain, but also managing FND.

Fibromyalgia is associated with hypersensitivity but not with abnormal pain modulation: evidence from QST trials and spinal fMRI

Article

Full-text available

Dec 2023

Widespread pain and hyperalgesia are characteristics of chronic musculoskeletal pain conditions, including fibromyalgia syndrome (FM). Despite mixed evidence, there is increasing consensus that these characteristics depend on abnormal pain augmentation and dysfunctional pain inhibition. Our recent investigations of pain modulation with individually adjusted nociceptive stimuli have confirmed the mechanical and thermal hyperalgesia of FM patients but failed to detect abnormalities of pain summation or descending pain inhibition. Furthermore, our functional magnetic resonance imaging evaluations of spinal and brainstem pain processing during application of sensitivity-adjusted heat stimuli demonstrated similar temporal patterns of spinal cord activation in FM and HC participants. However, detailed modeling of brainstem activation showed that BOLD activity during “pain summation” was increased in FM subjects, suggesting differences in brain stem modulation of nociceptive stimuli compared to HC. Whereas these differences in brain stem activation are likely related to the hypersensitivity of FM patients, the overall central pain modulation of FM showed no significant abnormalities. These findings suggest that FM patients are hyperalgesic but modulate nociceptive input as effectively as HC.

Improving magnetic resonance spectroscopy in the brainstem periaqueductal gray using spectral registration

Article

Full-text available

Oct 2023
MAGN RESON MED

Purpose Functional understanding of the periaqueductal gray (PAG), a clinically relevant brainstem region, can be advanced using ¹H‐MRS. However, the PAG's small size and high levels of physiological noise are methodologically challenging. This study aimed to (1) improve ¹H‐MRS quality in the PAG using spectral registration for frequency and phase error correction; (2) investigate whether spectral registration is particularly useful in cases of greater head motion; and (3) examine metabolite quantification using literature‐based or individual‐based water relaxation times. Methods Spectra were acquired in 33 healthy volunteers (50.1 years, SD = 17.19, 18 females) on a 3 T Philipps MR system using a point‐resolved spectroscopy (PRESS) sequence optimized with very selective saturation pulses (OVERPRESS) and voxel‐based flip angle calibration (effective volume of interest size: 8.8 × 10.2 × 12.2 mm³). Spectra were fitted using LCModel and SNR, NAA peak linewidths and Cramér‐Rao lower bounds (CRLBs) were measured after spectral registration and after minimal frequency alignment. Results Spectral registration improved SNR by 5% (p = 0.026, median value post‐correction: 18.0) and spectral linewidth by 23% (p < 0.001, 4.3 Hz), and reduced the metabolites' CRLBs by 1% to 15% (p < 0.026). Correlational analyses revealed smaller SNR improvements with greater head motion (p = 0.010) recorded using a markerless motion tracking system. Higher metabolite concentrations were detected using individual‐based compared to literature‐based water relaxation times (p < 0.001). Conclusion This study demonstrates high‐quality ¹H‐MRS acquisition in the PAG using spectral registration. This shows promise for future ¹H‐MRS studies in the PAG and possibly other clinically relevant brain regions with similar methodological challenges.

Pain Biomarkers in Fibromyalgia Syndrome: Current Understanding and Future Directions

Article

Full-text available

Jun 2023
INT J MOL SCI

Fibromyalgia is a complex and heterogeneous clinical syndrome, mainly characterized by the presence of widespread pain, possibly associated with a variety of other symptoms. Fibromyalgia can have an extremely negative impact on the psychological, physical and social lives of people affected, sometimes causing patients to experience dramatically impaired quality of life. Nowadays, the diagnosis of fibromyalgia is still clinical, thus favoring diagnostic uncertainties and making its clear identification challenging to establish, especially in primary care centers. These difficulties lead patients to undergo innumerable clinical visits, investigations and specialist consultations, thus increasing their stress, frustration and even dissatisfaction. Unfortunately, research over the last 25 years regarding a specific biomarker for the diagnosis of fibromyalgia has been fruitless. The discovery of a reliable biomarker for fibromyalgia syndrome would be a critical step towards the early identification of this condition, not only reducing patient healthcare utilization and diagnostic test execution but also providing early intervention with guideline-based treatments. This narrative article reviews different metabolite alterations proposed as possible biomarkers for fibromyalgia, focusing on their associations with clinical evidence of pain, and highlights some new, promising areas of research in this context. Nevertheless, none of the analyzed metabolites emerge as sufficiently reliable to be validated as a diagnostic biomarker. Given the complexity of this syndrome, in the future, a panel of biomarkers, including subtype-specific biomarkers, could be considered as an interesting alternative research area.

The periaqueductal grey in chronic low back pain: dysregulated metabolites and function

Preprint

Full-text available

Jun 2023

Mechanisms underlying chronic pain are insufficiently understood. Preclinical evidence suggests a potential contribution of excitatory glutamatergic and inhibitory GABAergic imbalances in pain-relevant brain areas, such as a lower excitatory/inhibitory tone in the brainstem periaqueductal grey (PAG). This cross-sectional magnetic resonance spectroscopy (MRS) study investigated whether a lower excitatory/inhibitory tone is also observed in the PAG of patients with non-specific chronic low back pain (CLBP) and whether this would relate to altered psychophysical measures of descending pain modulation and experimental pressure pain sensitivity. Specifically, the ratio between pooled glutamate and glutamine and GABA levels (Glx/GABA), Glx and GABA in the PAG were compared between CLBP patients and pain-free controls. Further, associations of Glx/GABA with conditioned pain modulation (CPM) effects and pressure pain thresholds (PPTs) were assessed. MRS was acquired on a 3T Philipps MR system using a point-resolved spectroscopy sequence optimized with very selective saturation pulses (OVERPRESS) and voxel-based flip angle calibration in a 1.1 mL volume of interest. Data from 41 CLBP patients (median [interquartile range]: 54 years [41 - 65], 22 females) and 29 age- and sex-matched controls (47 years [34 - 67], 17 females) fulfilled MRS quality criteria. CPM and PPTs were assessed at the lower back as most painful area and the non-dominant hand as pain-free control area. The CPM paradigm consisted of PPTs applied before, during (parallel CPM effect) and after a cold water bath and an ambient temperature water bath as control paradigm to identify 'true' CPM effects. In the PAG of CLBP patients, a lower Glx/GABA ratio, i.e. a lower excitatory/inhibitory tone, was observed (P = 0.002, partial η2 = 0.14) driven by decreased Glx (P = 0.012, partial η2 = 0.11) and increased GABA (P = 0.038, d = 0.46). CLBP patients showed disrupted associations between Glx/GABA and PPTs compared to controls in both areas (lower back: P = 0.004, partial η2 = 0.12; hand: P = 0.002, partial η2 = 0.16). In controls, lower Glx/GABA was associated with lower PPTs (lower back: r = 0.48, P = 0.009, hand: r = 0.53, P = 0.003), but this link was missing in CLBP patients (r's > -0.23, P's > 0.150). Additionally, CLBP patients with more severe clinical pain showed smaller CPM effects at the hand (rho = 0.54, P = 0.003). These findings suggest a dysfunction of the PAG in patients with CLBP and might indicate altered descending inhibition of deep tissue afferents.

General Sensory System and Taste

Chapter

Jan 2025

Neurophysiological and Psychosocial Mechanisms of Fibromyalgia: A Comprehensive Review and Call for An Integrative Model

Article

May 2023
NEUROSCI BIOBEHAV R

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Evaluation of the accuracy of several symptoms and domains in distinguishing patients diagnosed with fibromyalgia from healthy controls

Article

Full-text available

Jan 2016

Objectives: To assess the discriminative power of several symptoms and domains that may assist in the diagnosis of subjects with Fibromyalgia (FM). Methods: 79 individuals with FM and 66 healthy controls participated in the study. The potential domains proposed by the American College of Rheumatology (ACR) criteria were considered (Wolfe et al., 1990). Binary logistic regression and area under a ROC curve (AUC) were used to rank the importance of the variables in distinguishing patients from pain-free controls. Z values were then calculated to compare the AUC values obtained for each variable with that which yielded the highest AUC (reference standard). For each measure, the cut-offs that maximise sensitivity and specificity were also calculated. Results: The mean pressure pain threshold (PPT) yielded the highest discriminative power (AUC, 0.991) and was therefore chosen as the reference standard; considering an optimal cut- off ≤3.97, it correctly classified 95% of patients and 97% of controls. The discriminative powers of tender point count (cut-off ≥9), health-related quality of life (cut-off ≤63.27) and vitality (cut-off ≤46.97) were as good as that of the reference standard. Finally, items related to physical role and function, body pain, fatigue and memory loss showed adequate discriminative power, although slightly lower than that of the reference. Conclusions: In addition to pain, health-related quality of life and fatigue/vitality were confirmed as the best predictors of individuals with FM. The study findings indicate that tender point count and especially pressure pain threshold (measured with an algometer) continue to be key issues in the clinical assessment of subjects with FM relative to pain-free controls.

Fatigue and widespread pain in systemic lupus erythematosus and Sjögren's syndrome: symptoms of the inflammatory disease or associated fibromyalgia?

Article

Full-text available

Dec 2012

Fatigue and generalised pain are debilitating symptoms that negatively impact the quality of life in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). Chronic widespread musculoskeletal pain and fatigue are the clinical hallmarks of fibromyalgia (FM), a clinical entity which can be associated to connective tissue disease. The aim of the present study was to assess the prevalence of FM syndrome, fatigue and widespread pain in SLE and pSS patients and to evaluate the contribution of inflammatory disease and FM on those constitutional symptoms. Fifty SLE and 50 pSS patients were enrolled in the study. Patients rated fatigue, pain, and disease activity using a 100-mm visual analogue scale and completed the Health Assessment Questionnaire and the Fibromyalgia Impact Questionnaire. Zung depression and anxiety scales were used to quantify mood disorders. Tender points were evaluated using an algometer. Disease activity score as evaluated for each SLE and pSS patient. Fibromyalgia has been diagnosed in a significantly higher percentage of SLE patients than pSS patients (32% vs. 18%, p=0.022) even if the percentage of patients reporting fatigue and pain was higher among pSS patients. No correlation with disease activity was observed in either group of patients. FM seems to contribute to constitutional symptoms more in SLE than in pSS, suggesting a different underlying cause of fatigue and widespread pain in these two different connective tissue diseases.

Algo-dysfunctional syndromes: A critical digest of the recent literature

Article

Full-text available

Mar 2015

The etiopathogenesis of the algo-dysfunctional syndromes, which include chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome, is still debated, but it is widely accepted that it is best described by a multifactorial model that include genes, environmental factors such as external infections, inflammation, dietary habits, impaired endogenous cortisol production, the aberrant activation of some areas of the central nervous system, and small peripheral nervous fibre damage. This complexity suggests that they should be managed by means of a multidisciplinary approach involving the use of both pharmacological and non-pharmacological treatments. The aim of this review is to discuss the most recent scientific acquisitions concerning these syndromes and their treatment.

Hyperexcitability in pain matrices in patients with fibromyalgia

Article

Full-text available

Mar 2015

Emerging evidence associates fibromyalgia (FM) with pain system dysfunction. In this study, using laser evoked potentials (LEPs) and paired laser stimuli, we tested excitability in the pain matrices and sought possible changes in patients with FM. In 20 patients with FM and 15 healthy subjects, after recording control nociceptive system-mediated Aδ- and C-fibre-related LEPs, we measured excitability in the pain matrices by testing the Aδ-LEP conditioned by a preceding C-LEP. No difference was found in control LEP amplitudes for Aδ- or C-fibres between patients and healthy subjects. Conversely, the Aδ-LEP amplitude, conditioned by a preceding C-LEP, was significantly higher in patients than in healthy subjects (p<0.001). Objective evidence from increased conditioned Aδ-LEP amplitudes reflecting hyperexcitability in the pain matrices in FM, provides diagnostically useful information and might help in developing new therapeutic approaches.

Key Mechanisms Mediating Fibromyalgia.

Article

Full-text available

Mar 2015

The periaqueductal gray and descending pain modulation: Why should we study them and what role do they play in chronic pain?

Article

Full-text available

Feb 2015

Here, we discuss the significance of a recent study by Yu et al. (Neuroimage: Clinical 6: 100-108, 2014). The authors examined functional connectivity of a key node of the descending pain modulation pathway, the periaqueductal gray (PAG), in chronic back pain patients. Altered PAG connectivity to pain-related regions was found; we place results within the context of recent literature and emphasize the importance of understanding the descending component of pain in pain research.

Neuroimaging of chronic pain

Article

Jun 2015

Tobias Schmidt-Wilcke

Chronic pain is an important public health problem, and there is a need to understand the mechanisms that lead to pain chronification. From a neurobiological perspective, the mechanisms contributing to the transition from acute to subacute and chronic pain are heterogeneous and are thought to take place at various levels of the peripheral and central nervous system. In the past decade, brain imaging studies have shed light on neural correlates of pain perception and pain modulation, but they have also begun to disentangle neural mechanisms that underlie chronic pain. This review summarizes important and recent findings in pain research using magnetic resonance tomography. Especially new developments in functional, structural and neurochemical imaging such as resting-state connectivity and γ-aminobutyric acid (GABA) spectroscopy, which have advanced our understanding of chronic pain and which can potentially be integrated in clinical practice, will be discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Relationship between sympathetic activity and pain intensity in fibromyalgia

Article

Mar 2015

Fibromyalgia (FM) is a syndrome characterised by chronic musculoskeletal pain, hyperalgesia on specific areas of tenderness (tender points) and by an autonomic nervous system dysfunction consistent with sympathetic overactivity. It is not known whether there is any relationship between the amount of cardiovascular sympathetic activity and the magnitude of pain. Our objective was to assess this potential relationship in patients with FM. Electrocardiogram, finger blood pressure, respiration and post-ganglionic sympathetic discharge activity (muscle sympathetic nerve activity, MSNA) were continuously recorded at rest in 25 patients with primary FMS. The autonomic profile was assessed by MSNA and spectral indices of cardiac sympathetic (LFRR) and vagal (HFRR) modulation and of sympathetic vasomotor control (LF-SAP) computed by spectrum analysis of RR and systolic arterial pressure (SAP) variability. Cardiac baroreflex function was evaluated by the index α (αLF). Baroreceptor modulation of the sympathetic vasomotor control (sBRS) was assessed by the MSNA/diastolic pressure relationship. Pain intensity was linearly correlated with LFRR/HFRR (r2=0.21; p=0.03), LFSAP (r2=0.26; p=0.02) and MSNA (burst rate) (r2=0.45; p=0.003). Pain intensity was inversely correlated with the αLF index (r2=0.24; p=0.02) and the sBRS (r2=0.28; p=0.03). Thus, the higher the sympathetic drive to the heart and vessels, the higher the magnitude of chronic pain. Also, the gains of both the cardiac and MSNA baroreceptor control were inversely related to the pain intensity. These findings raise the theoretical possibility that in FM patients the use of anti-adrenergic agents might lessen chronic pain intensity by reducing the underlying excessive sympathetic activity.

Does body composition differ between fibromyalgia patients and controls? The al-Ándalus project

Article

Jan 2015

OBJECTIVES: To characterise the anthropometric and body composition profile of a sample of fibromyalgia women and men from southern Spain and compare them with non-fibromyalgia controls. METHODS: The cross-sectional study comprised 566 (51.9±8.3 years) fibromyalgia women vs. 249 (49.3±9.9 years) control women; and 24 (47.0±8.4 years) fibromyalgia men vs. 56 (49.7±11.5 years) control men. Body composition and cardiorespiratory fitness were assessed by means of a bioelectric impedanciometer and the 6-minute walk test, respectively. RESULTS: All body composition para-meters (except muscle mass) differed between fibromyalgia and control women (all, p<0.01) even after controlling for several key variables (all, p<0.05). The effect sizes observed were small-medium. When cardiorespiratory fitness was included as covariate, body composition was no longer different between the women study groups. No differences in body composition were observed between fibromyalgia and control men (all, p>0.05). Weight status differed between women groups, with 11% lower normal-weight and 17% higher obesity prevalence for the fibromyalgia women group (p<0.001), but not between men groups (p=0.711). Seventy-two percent of the fibromyalgia women and 79% of the fibromyalgia men were overweight-obese. Sixty-one percent of the control women and 83% of the control men were overweight-obese. CONCLUSIONS: Obesity is a greater common condition among fibromyalgia women compared to their counterparts from southern Spain, which might be explained by lower levels of cardiorespiratory fitness in fibromyalgia. However, fibromyalgia and control men do not differ on either body composition or weight status, in spite of the lower cardiorespiratory fitness found in the fibromyalgia men group.

How important are the psychological aspects in fibromyalgic syndrome?

Article